Reliability of GRBAS evaluation of voice quality in children who have a history of airway reconstruction surgery and how this compares to parental report of voice-related quality of life

Voice evaluation includes laryngoscopy, perceptual judgement of voice quality, evaluation of respiratory function, acoustic analysis of the voice signal and patient reported subjective impact of voice on quality of life. This is recommended in adults (Dejonkere et al 2001) and children (Cohen et al 2012). Perceptual evaluation of voice often follows the CAPE-V (ASHA 2002) or GRBAS (Hirano 1981). Children requiring laryngotracheal reconstruction (LTR) surgery tend to have this procedure during infancy, where subglottic stenosis forms following intubation in medically fragile or premature infants. Clinicians require reliable measures, particularly where there is a degree of subjectivity. Aspects of the CAPE-V show a high degree of reliability in rating of severity, pitch, breathiness and roughness (Krival et al 2007, Kelchner et al 2008). UK clinicians favour the GRBAS though there is little published information about reliability in a paediatric population. Comparison of clinician perceptual evaluation with patient report shows weak agreement in adults (Karnell et al 2006) reinforcing the need for both measurements. The extent to which the same is the case in children needs further exploration

Cross-sectional follow up of voice outcomes in children who have a history of airway reconstruction surgery

Objectives - This study reports vocal function in a cross-section of children with subglottic stenosis. Each child had a history of laryngotracheal reconstruction and/or cricotracheal resection surgery. Vocal function was measured using laryngoscopy, acoustic analysis, perceptual evaluation and impact of voice on quality of life.  Design - All patients aged >5 years with history of laryngotracheal reconstruction and/or cricotracheal resection surgery at the Scottish National Complex Airways service were invited to participate.  Setting - Data was gathered in the Royal Hospital for Children in Glasgow in a single out-patient appointment. Participants - Twelve out of fifty-six former patients (aged 5 – 27) provided a voice sample and eleven consented to awake laryngoscopy. All consented for detailed evaluation of their medical records.  Main outcome measures - Acoustic analysis of fundamental frequency and pitch perturbation was conducted on sustained vowel [a]. Perceptual evaluation was conducted by four trained listeners on a series of spoken sentences. Impact on quality of life was measured using the Paediatric Voice Related Quality of Life questionnaire. Laryngeal function was descriptively evaluated.  Results - Four children had normal voice acoustically, perceptually and in relation to voice related quality of life. One of these had vocal fold nodules unrelated to surgical history. Two other children had ‘near normal’ vocal function, defined where most voice measurements fell within the normal range.  Conclusions - Normal or ‘near normal’ voice is a possible outcome for children who have had this surgery. Where there is an ongoing complex medical condition, voice outcome may be poorer

Perceptual evaluation of voice disorder in children who have had laryngotracheal reconstruction surgery and the relationship between clinician perceptual rating of voice quality and parent proxy/child self-report of voice related quality of life

Reliability of the GRBAS tool for perceptual evaluation of paediatric voice disorder is measured in this study of children with a history of laryngotracheal reconstruction surgery (LTR). Additionally, the relationship between parent proxy/child self-report of voice related quality of life with clinician perceptual rating of voice quality is analysed. Eleven children with a history of LTR provided voice recordings following the stimuli set by the CAPE-V protocol. Subjective impact of voice quality on life was measured using the Pediatric Voice-Related Quality of Life Questionnaire. Four trained judges rated the sound files according to both the GRBAS and CAPE-V protocol. Intraclass correlation coefficients were high for both intrarater and interrater judgements across all parameters of the GRBAS protocol, and a strong correlation was found between the Grade rating of the GRBAS and the Overall Severity rating of the CAPE-V. Some elements of parent proxy reporting of VRQOL were significantly negatively correlated with clinician perceptual rating of voice quality, while there was no significant relationship between child self-report and clinician perceptual rating

Viruses and anti-viral agents

No abstract available

Fusion of the BCL9 HD2 domain to E1A increases the cytopathic effect of an oncolytic adenovirus that targets colon cancer cells

Swiss Cancer League, Swiss National Science Foundation and SNSF NCCR Molecular Oncology ProgrammeBackground: The Wnt signaling pathway is activated by mutations in the APC and beta-catenin genes in many types of human cancer. beta-catenin is stabilized by these mutations and activates transcription in part by acting as a bridge between Tcf/LEF proteins and the HD2 domain of the BCL9 coactivator. We have previously described oncolytic adenoviruses with binding sites for Tcf/LEF transcription factors inserted into the early viral promoters. These viruses replicate selectively in cells with activation of the Wnt pathway. To increase the activity of these viruses we have fused the viral transactivator E1A to the BCL9 HD2 domain. Methods: Luciferase assays, co-immunoprecipitation and Western blotting, immunofluorescent cell staining and cytopathic effect assays were used to characterize the E1A-HD2 fusion protein and virus in vitro. Growth curves of subcutaneous SW620 colon cancer xenografts were used to characterize the virus in vivo. Results: The E1A-HD2 fusion protein binds to beta-catenin in vivo and activates a Tcf-regulated luciferase reporter better than wild-type E1A in cells with activated Wnt signaling. Expression of the E1A-HD2 protein promotes nuclear import of beta-catenin, mediated by the strong nuclear localization signal in E1A. Tcf-regulated viruses expressing the fusion protein show increased expression of viral proteins and a five-fold increase in cytopathic effect (CPE) in colorectal cancer cell lines. There was no change in viral protein expression or CPE in HeLa cells, indicating that E1A-HD2 viruses retain selectivity for cells with activation of the Wnt signaling pathway. Despite increasing the cytopathic effect of the virus in vitro, fusion of the HD2 domain to E1A did not increase the burst size of the virus in vitro or the anti-tumor effect of the virus in an SW620 xenograft model in vivo. Conclusion: Despite an increase in the nuclear pool of beta-catenin, the effects on viral activity in colon cancer cells were small, suggesting that factors acting downstream of beta-catenin are limiting for viral replication and toxicity in these cells. The approach of fusing E1A to a protein domain implicated in oncogenic signaling could be used to selectively increase the activity of oncolytic viruses targeting several other pathways defective in cancer.Publisher PDFPeer reviewe

Finding the instability strip for accreting pulsating white dwarfs from Hubble Space Telescope and optical observations

Time-resolved low resolution Hubble Space Telescope ultraviolet spectra together with ground-based optical photometry and spectra are used to constrain the temperatures and pulsation properties of six cataclysmic variables containing pulsating white dwarfs (WDs). Combining our temperature determinations for the five pulsating WDs that are several years past outburst with past results on six other systems shows that the instability strip for accreting pulsating WDs ranges from 10,500 to 15,000 K, a wider range than evident for ZZ Ceti pulsators. Analysis of the UV/optical pulsation properties reveals some puzzling aspects. While half the systems show high pulsation amplitudes in the UV compared to their optical counterparts, others show UV/optical amplitude ratios that are less than one or no pulsations at either wavelength region

Atrial natriuretic factor increases splenic microvascular pressure and fluid extravasation in the rat

The spleen is an important site of atrial natriuretic factor (ANF)-induced fluid extravasation into the systemic lymphatic system. The mechanism underlying this process was studied in a blood-perfused (1 ml min−1) rat spleen using the double occlusion technique. To ensure that our observations were spleen specific, a similar protocol was repeated in the hindquarters.Rat ANF(1-28), infused into the splenic artery of anaesthetized male rats, caused a dose-dependent (0.3-59 pmol min−1) increase in microvascular pressure from 11.3 ± 0.7 to 14.9 ± 0.5 mmHg and in post-capillary resistance from 7.2 ± 0.6 to 10.1 ± 1.1 mmHg ml−1. ANF elicited no change in splenic pre-capillary resistance or in hindquarter haemodynamics.Intrasplenic ANF (6.5 pmol min−1) caused a sustained increase in intrasplenic fluid efflux from 0.1 ± 0.1 to 0.3 ± 0.1 ml min−1, and in capillary filtration coefficient (Kf) from 1.2 ± 0.5 to 2.4 ± 0.6 ml mmHg−1 min−1 (100 g tissue)−1.Mechanical elevation of splenic intravascular pressure (from 11.3 ± 0.7 to 22.4 ± 0.2 mmHg) significantly increased intrasplenic fluid extravasation (from 0.4 ± 0.3 to 1.4 ± 0.3 ml min−1).The natriuretic peptide receptor-C (NPRC)-specific agonist C-ANF(4-23) (12.5 and 125 pmol min−1) did not alter splenic intravascular pressure or pre-/post-capillary resistance.The ANF antagonist A71915 (8.3 and 83 pmol min−1), which blocks ANF-stimulated cGMP production via natriuretic peptide receptor-A (NPRA), inhibited the ANF-induced changes in splenic microvascular pressure and post-capillary resistance.It is concluded that ANF enhances the extravasation of isoncotic fluid from the splenic vasculature both by raising intrasplenic microvascular pressure (increased post-capillary resistance) and by increasing filtration area. The constrictive activity of ANF on the splenic vasculature is mediated through NPRA